Earlier this year my friend and colleague Mark Buller passed away. Mark was a noted virologist and a professor at Saint Louis University. He was struck by a car while riding his bicycle home from the lab, and died from his injuries. Here is Mark's obituary as published by the university.

In 2014 and 2015, Mark and I served as advisors to a WHO scientific working group on synthetic biology and the variola virus (the causative agent of smallpox). In 2016, we wrote the following, previously un-published, response to an "Op-Doc" that appeared in the New York Times. In a forthcoming post I will have more to say about both my experience with the WHO and my thoughts on the recent publication of a synthetic horsepox genome. For now, here is the last version (circa May, 2016) of the response Mark I and wrote to the Op-Doc, published here as my own memorial to Professor Buller.

Variola virus is still needed for the development of smallpox medical countermeasures

On May 17, 2016 Errol Morris presented a short movie entitled “Demon in the Freezer” [note: quite different from the book of the same name by Richard Preston] in the Op-Docs section of the on-line New York Times. The piece purported to present both sides of the long-standing argument over what to do with the remaining laboratory stocks of variola virus, the causative agent of smallpox, which no longer circulates in the human population.

Since 1999, the World Health Organization has on numerous occasions postponed the final destruction of the two variola virus research stocks in Russia and the US in order to support public health related research, including the development of smallpox molecular diagnostics, antivirals, and vaccines.

“Demon in the Freezer” clearly advocates for destroying the virus. The Op-Doc impugns the motivation of scientists carrying out smallpox research by asking: “If given a free hand, what might they unleash?” The narrative even suggests that some in the US government would like to pursue a nefarious policy goal of “mutually assured destruction with germs”. This portion of the movie is interlaced with irrelevant, hyperbolic images of mushroom clouds. The reality is that in 1969 the US unilaterally renounced the production, storage or use biological weapons for any reason whatsoever, including in response to a biologic attack from another country. The same cannot be said for ISIS and Al-Qaeda. In 1975 the US ratified the 1925 Geneva Protocol banning chemical and biological agents in warfare and became party to the Biological Weapons Convention that emphatically prohibits the use of biological weapons in warfare.

“Demon in the Freezer” is constructed with undeniable flair, but in the end it is a benighted 21st century video incarnation of a middling 1930's political propaganda mural. It was painted with only black and white pigments, rather than a meaningful palette of colors, and using a brush so broad that it blurred any useful detail. Ultimately, and to its discredit, the piece sought to create fear and outrage based on unsubstantiated accusations.

Maintaining live smallpox virus is necessary for ongoing development and improvement of medical countermeasures. The first-generation US smallpox vaccine was produced in domesticated animals, while the second-generation smallpox vaccine was manufactured in sterile bioreactors; both have the potential to cause serious side effects in 10-20% of the population. The third generation smallpox vaccine has an improved safety profile, and causes minimal side effects. Fourth generation vaccine candidates, based on newer, lower cost, technology, will be even safer and some are in preclinical testing. There remains a need to develop rapid field diagnostics and an additional antiviral therapy for smallpox.

Continued vigilance is necessary because it is widely assumed that numerous undeclared stocks of variola virus exist around the world in clandestine laboratories. Moreover, unsecured variola virus stocks are encountered occasionally in strain collections left behind by long-retired researchers, as demonstrated in 2014 with the discovery of 1950s vintage variola virus in a cold room at the NIH. The certain existence of unofficial stocks makes destroying the official stocks an exercise in declaring “victory” merely for political purposes rather than a substantive step towards increasing security. Unfortunately, the threat does not end with undeclared or forgotten samples.

In 2015 a WHO Scientific Working Group on Synthetic Biology and Variola Virus and Smallpox determined that a “skilled laboratory technician or undergraduate student with experience of working with viruses” would be able to generate variola virus from the widely available genomic sequence in “as little as three months”. Importantly, this Working Group concluded that “there will always be the potential to recreate variola virus and therefore the risk of smallpox happening again can never be eradicated.” Thus, the goal of a variola virus-free future, however laudable, is unattainable. This is sobering guidance on a topic that requires sober consideration.

We welcome increased discussions of the risk of infectious disease and of public health preparedness. In the US these topics have too long languished among second (or third) tier national security conversations. The 2014 West Africa Ebola outbreak and the current Congressional debate over funding to counter the Zika virus exemplifies the business-as-usual political approach of throwing half a bucket of water on the nearest burning bush while the surrounding countryside goes up in flames. Lethal infectious diseases are serious public health and global security issues and they deserve serious attention.

The variola virus has killed more humans numerically than any other single cause in history. This pathogen was produced by nature, and it would be the height of arrogance, and very foolish indeed, to assume nothing like it will ever again emerge from the bush to threaten human life and human civilization. Maintenance of variola virus stocks is needed for continued improvement of molecular diagnostics, antivirals, and vaccines. Under no circumstances should we unilaterally cripple those efforts in the face of the most deadly infectious disease ever to plague humans. This is an easy mistake to avoid.

Mark Buller, PhD, was a Professor of Molecular Microbiology & Immunology at Saint Louis University School of Medicine, who passed away on February 24, 2017. Rob Carlson, PhD, is a Principal at the engineering and strategy firm Biodesic and a Managing Director of Bioeconomy Capital.

The authors served as scientific and technical advisors to the 2015 WHO Scientific Working Group on Synthetic Biology and Variola Virus.